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Updated: Aug 6, 2026
Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue
Published on: January 19, 2019
Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy
Teresa Ravizza1, Sian-Marie Lucas, Silvia Balosso
1Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
Purpose:
Cytokines and related inflammatory mediators are rapidly synthesized in the brain during seizures. We previously found that intracerebral administration of interleukin-1 (IL-1)-beta has proconvulsant effects, whereas its endogenous receptor antagonist (IL-1Ra) mediates potent anticonvulsant actions in various models of limbic seizures. In this study, we investigated whether seizures can be effectively inhibited by blocking the brain production of IL-1beta, by using selective inhibitors of interleukin-converting enzyme (ICE/caspase-1) or through caspase-1 gene deletion.
Methods:
Caspase-1 was selectively blocked by using pralnacasan or VX-765. IL-1beta release was induced in mouse organotypic hippocampal slice cultures by proinflammatory stimuli [lipopolysaccharide (LPS) + adenosine triphosphate (ATP)] and measured with enzyme-linked immunosorbent assay (ELISA). IL-1beta production during seizures was measured in the rat hippocampus by Western blot. Seizures were induced in freely moving mice and rats by intrahippocampal injection of kainic acid and recorded by EEG analysis.
Results:
Caspase-1 inhibition reduced the release of IL-1beta in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 microg) or VX-765 (intraperitoneal, 25-200 mg/kg) to rats blocked seizure-induced production of IL-1beta in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration. Mice with caspase-1 gene deletion showed a 70% reduction in seizures and an approximate fourfold delay in their onset.
Conclusions:
Inhibition of caspase-1 represents an effective and novel anticonvulsive strategy, which acts by selectively reducing the brain availability of IL-1beta.
Insights
Blocking caspase-1 (interleukin-converting enzyme) effectively reduces brain interleukin-1 beta (IL-1beta) production, significantly inhibiting seizures. This novel strategy delays seizure onset and reduces seizure duration and frequency.
Area of Science:
- Neuroscience
- Inflammation Research
- Epilepsy Research
Background:
- Cytokines and inflammatory mediators are rapidly synthesized in the brain during seizures.
- Interleukin-1 beta (IL-1beta) has proconvulsant effects, while its antagonist (IL-1Ra) is anticonvulsant.
- Previous research indicates a role for IL-1beta in seizure activity.
Purpose of the Study:
- To investigate the efficacy of inhibiting brain IL-1beta production in preventing seizures.
- To evaluate the use of selective interleukin-converting enzyme (ICE/caspase-1) inhibitors or gene deletion for seizure inhibition.
Main Methods:
- Caspase-1 was inhibited using pralnacasan or VX-765 in rodent models.
- IL-1beta release was measured in hippocampal slices and rat hippocampus.
- Seizures were induced via kainic acid injection and monitored using EEG analysis.
Main Results:
- Caspase-1 inhibition reduced IL-1beta release in vitro and in vivo.
- Drug administration delayed seizure onset by twofold and reduced duration by 50% in rats.
- Mice with caspase-1 gene deletion exhibited a 70% reduction in seizures and a fourfold delay in onset.
Conclusions:
- Inhibition of caspase-1 is a novel and effective anticonvulsive strategy.
- This approach selectively reduces brain IL-1beta availability, thereby mitigating seizures.
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